When legal and important areas of interest collide – the impact of patent law on interchangeability

A company about to launch a prescription medicinal product must necessarily take several legal aspects into account. One such constantly relevant issue is which patent rights may affect the launch. Even if the relevant substance itself is not patent- protected by a third party, there may be patent rights in relation to, for example, a certain dosage regimen or a certain form of administration.

In some cases, patent-related issues may also spill over into other legal areas. The company launching the product may have ensured through various measures/limitations that the launch and sale of the product does not constitute any patent infringement, but as a result of these measures/limitations, it might face problems with the regulatory authorities.

One such problem relevant in Sweden concerns the issue of interchangeability or generic substitution. Typically, for  a launch of generic medicinal product in Sweden to be commercially attractive, it is of great importance for it to be placed in the same interchangeability group (Sw. utbytbarhetsgrupp) as the reference medicinal product. This as the latter, depending on the functionality of the prescription system, will be the one prescribed by the physicians.

According to the Swedish Medicinal Products Act (the Act), the Swedish Medical Products Agency (the Agency), when a marketing authorisation has been granted for a medicinal product, must decide whether the product is interchangeable with another – primarily the reference product. The Act further states that medicinal products are interchangeable only if they can be considered equivalent. In practice, medicinal products have been considered “equivalent” provided that they:

(a) are approved as medicinal products;

(b) contain the same active ingredient(s);

(c) contain the same amount of the active ingredient(s);

(d) have the same form of preparation; and

(e) have been assessed as bioequivalent/therapeutically equivalent.

This list of requirements generally does not cause any concerns to generic companies.  However, there is an additional (potential) obstacle to overcome, and that is the Agency’s remaining overall assessment of the generic medicinal product’s effect and safety.  In other words: even if the generic and the reference product are equivalent in the meaning of the Act, there may be differences that, in the opinion of the Agency, constitute obstacles to interchangeability.

On its website, the Agency lists several examples of such differences that could constitute obstacles to interchangeability, one of which is that “some essential part of the product information is missing or contradictory”. Differences in product information can thus be considered an obstacle to interchangeability, even if the products as such are equivalent.  As initially indicated, generic companies are sometimes forced to make adjustments to the product information to avoid patent infringement – a concept known as “skinny labelling”. The legislator has foreseen this, and a marketing authorisation can thus be granted for a generic even if its product information differs from the reference product’s information, provided that the difference is due to patent law considerations.  Hence, Article 11 of Directive 2011/83 stipulates the following:

For authorisations under Article 10, those parts of the summary of product characteristics of the reference medicinal product referring to indications or dosage forms which were still covered by patent law at the time when a generic medicine was marketed need not be included.

But: In this situation, the generic company risks getting caught between two different regulations. On the one hand, an adjustment of the product information (SmPC + package leaflet) must be made to avoid patent infringement. On the other hand, the adjustments to the product information may result in the Agency finding reasons to place the generic medicine in a separate interchangeability group (even if the generic product is equivalent to the reference product), on the basis of the aforementioned exception: that, in the opinion of the Agency, some essential part of the product information is missing or contradictory.

Patent law considerations may thus push the generic company into a kind of regulatory dead end.  However, it should be borne in mind that the differences in product information must have an impact on the effect or safety of the generic medicine for the difference to constitute an obstacle to interchangeability.  In a recent case at the Administrative Court in Uppsala, a generic company appealed the Agency’s decision not to place its generic product in the same interchangeability group as the reference product. The generic company had been granted marketing authorisation for a medicine provided in capsule form – same as the reference product – and all the requirements (a) – (e) above were fulfilled.

However, to respect a patent regarding a special form of administration for patients with swallowing difficulties – e.g. breaking the capsule and mixing the capsule contents with a teaspoon of apple sauce (with nothing else, and no more or less than a teaspoon) – it was stated in the package leaflet for the generic that it should not be used by patients with swallowing difficulties. This represented a difference from the reference product’s package leaflet, according to which the primary message was the same – the capsules were to be swallowed whole and not to be taken together with any foodstuff, but also that patients with swallowing difficulties could break the capsules and mix the contents with a teaspoon of apple sauce. The Agency argued that this difference posed a safety risk, as patients with a swallowing difficulty receiving the generic might administer the capsule contents using a different type of food (or different amount) than what had been confirmed as safe in clinical studies. To make the point more clearly, the patient’s absorption of the relevant active substance could be strongly affected if taken with food (the concentration of the active substance increased, which could potentially lead to serious side effects). According to the Agency, patients could thus potentially suffer serious side effects. Consequently, the Agency found that there was an obstacle to interchangeability, despite the products being equivalent. The Agency in its appealed decision ignored inter alia the facts that:

• The prescribing physicians have a duty to inform about differences and in relation to a medicinal product which could potentially cause dangerous side effects if taken together with food and especially for patients with swallowing difficulties, this duty could be expected to be fulfilled;
• The prescribing physicians have, if they believe that the difference is relevant, a duty and opportunity to block generic substitution at the pharmacies in the prescription;
• The pharmacists expediting against the prescription have a duty to inform about differences and in relation to a medicinal product that could potentially cause dangerous side effects if taken together with food, and especially in the case of patients with swallowing difficulties, this duty could be expected to be fulfilled;
• The patients would have to ignore the information they have been given and ignore the clear warning texts in the generic product information; and
• The patients, who must have had a previous habit of breaking capsules of the reference product and mixing the contents with a teaspoon of apple sauce, would in order to be exposed to a safety concern, suddenly in contrast with the strong warnings and previous information and habit, break the capsules and mix the contents with other foodstuffs or other quantities. Notably, if they broke the capsules and mixed the contents with a teaspoon of apple sauce, there was no identified risk. On the contrary, the products were considered equivalent.

As mentioned, the Agency’s decision was appealed to the Administrative Court in Uppsala. However, the appeal has been withdrawn as the patent-related issue was resolved. Hence, it remains uncertain how this type of collision between two legal areas – patent law and the regulatory provisions on interchangeability – should be dealt with. In the present case, there were the safety concerns in relation to the underlying general preference of generic competition to be assessed and respected. These latter are not typically interests that are weighed against each other, but the effects of their application and effectiveness must be considered.  Notably, in Sweden, effective market access relies heavily on the interchangeability/substitution system.

In summary, on the one hand, one could or perhaps even should respect the Agency’s rather far-reaching safety concerns but on the other hand, marginally relevant patent rights could, although respected, indirectly be allowed to effectively delay generic competition. If this is acceptable is probably not possible to have a firm opinion on at a general level but the circumstances in the individual case should and must be considered and the safety concerns realistic and objective.